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Apr 27, 2015 - 1Pulmonary Division, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. 2Faculty ...... J Appl Physiol 87, 1802–1812.
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J Physiol 593.14 (2015) pp 3147–3157

Dopamine receptor blockade improves pulmonary gas exchange but decreases exercise performance in healthy humans Vincent Tedjasaputra1,2 , Tracey L. Bryan1 , Sean van Diepen3,4 , Linn E. Moore1,2 , Melissa M. Bouwsema1,2 , Robert C. Welsh4 , Stewart R. Petersen2 and Michael K. Stickland1,5 1

Pulmonary Division, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada Faculty of Physical Education and Recreation, University of Alberta, Edmonton, Alberta, Canada 3 Division of Critical Care, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada 4 Division of Cardiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada 5 G. F. MacDonald Centre for Lung Health, Covenant Health, Edmonton, Alberta, Canada

The Journal of Physiology

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Key points

r At rest, dopamine induces recruitment of intrapulmonary arteriovenous anastomoses (IPAVA) and increases venous admixture (i.e. Q˙ s /Q˙ t ).

r Dopamine increases during exercise, and may be partly responsible for exercise-induced IPAVA recruitment.

r In this study, we antagonized dopamine receptors with metoclopramide, and observed improved pulmonary gas exchange but no difference in IPAVA recruitment during exercise.

r Dopamine blockade decreased cardiac output at peak exercise, resulting in decreased exercise performance.

r Increasing endogenous dopamine is important for the normal healthy response to exercise. Abstract Pulmonary gas exchange, as evaluated by the alveolar–arterial oxygen difference (A-aD O2 ), is impaired during intense exercise, and has been correlated with recruitment of intrapulmonary arteriovenous anastomoses (IPAVA) as measured by agitated saline contrast echocardiography. Previous work has shown that dopamine (DA) recruits IPAVA and increases venous admixture (Q˙ s /Q˙ t ) at rest. As circulating DA increases during exercise, we hypothesized that A-aD O2 and IPAVA recruitment would be decreased with DA receptor blockade. Twelve healthy males (age: 25 ± 6 years, V˙ O2 max : 58.6 ± 6.5 ml kg−1 min−1 ) performed two incremental staged cycling exercise sessions after ingestion of either placebo or a DA receptor blocker (metoclopramide 20 mg). Arterial blood gas, cardiorespiratory and IPAVA recruitment (evaluated by agitated saline contrast echocardiography) data were obtained at rest and during exercise up to 85% of V˙ O2 max . On different days, participants also completed incremental exercise tests and exercise tolerance (time-to-exhaustion (TTE) at 85% of V˙ O2 max ) with or without dopamine blockade. Compared to placebo, DA blockade did not change O2 consumption, CO2 production, or respiratory exchange ratio at any intensity. At 85% V˙ O2 max , DA blockade decreased A-aD O2 , increased arterial O2 saturation and minute ventilation, but did not reduce IPAVA recruitment, suggesting that positive saline contrast is unrelated to A-aD O2 . Compared to placebo, DA blockade decreased maximal cardiac output, V˙ O2 max and TTE. Despite improving pulmonary gas exchange, blocking dopamine receptors appears to be detrimental to exercise performance. These findings suggest that endogenous dopamine is important to the normal cardiopulmonary response to exercise and is necessary for optimal high-intensity exercise performance.

 C 2015 The Authors. The Journal of Physiology  C 2015 The Physiological Society

DOI: 10.1113/JP270238

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V. Tedjasaputra and others

J Physiol 593.14

(Received 22 January 2015; accepted after revision 27 April 2015) Corresponding author Dr. M. Stickland: 3-135 Clinical Sciences Building, Edmonton, Alberta, Canada, T6G 2J3. Email: [email protected] Abbreviations A-a D O2 , alveolar–arterial oxygen difference; BP, blood pressure; DA, dopamine; IPAVA, intrapulmonary arteriovenous anastomoses; P aCO2 , partial pressure of arterial CO2 ; P AO2 , partial pressure of alveolar O2 ; P aO2 , partial pressure of arterial O2 ; PAP, pulmonary arterial pressure; PVR, pulmonary vascular resistance; Q˙ s /Q˙ t , venous admixture-fraction of shunted blood to total cardiac output; RER, respiratory exchange ratio; S aO2 , percentage arterial O2 saturation; S pO2 , percentage arterial O2 saturation estimated by pulse oximetry; TTE, time-to-exhaustion; V˙ A /Q˙ , ventilation–perfusion inequality; V˙ CO2 , carbon dioxide production; V˙ O2 , oxygen consumption.

Introduction Intense aerobic exercise has been shown to decrease the efficiency of gas exchange in highly trained humans, as demonstrated by an increase in the alveolar–arterial oxygen difference (A-aD O2 ) (Dempsey et al. 1984; Hammond et al. 1986). Increased A-aD O2 during exercise was classically thought to be a result of diffusion O2 limitation (Dempsey et al. 1984) or V˙ A /Q˙ inequality (Dempsey et al. 1984; Schaffartzik et al. 1992; Hopkins et al. 1999) secondary to transient interstitial pulmonary oedema or reduced pulmonary transit time. More recent research suggests that intrapulmonary arteriovenous anastomoses (IPAVA), as detected by agitated saline contrast echocardiography, are recruited during exercise (Stickland et al. 2004; Eldridge et al. 2004), and appear related to gas exchange impairment (Stickland et al. 2004). However, this anatomical evidence of IPAVA is in contrast to the considerable inert gas data which has not shown measurable right-to-left shunt during exercise (Wagner et al. 1986; Hopkins et al. 1994; Rice et al. 1999). Thus, the mechanism of IPAVA recruitment and its association with increases in A-aD O2 during heavy exercise is the subject of an unresolved debate (Hopkins et al. 2009b,2009c; Lovering et al. 2009a). During exercise, endogenous dopamine (DA) concentrations increase curvilinearly with intensity (Hopkins et al. 2009a). Importantly, there is evidence that dopamine causes gas exchange impairment, as dopamine infusion increases venous admixture (Q˙ s /Q˙ t ) in resting supine humans (Bryan et al. 2012) and increases right-to-left shunt (V˙ A /Q˙ = 0 as detected by the multiple inert gas elimination technique; MIGET) in critically ill patients with pre-existing shunt (Rennotte et al. 1989). Dopamine also decreases pulmonary vascular resistance secondary to vasodilatation in the pulmonary vasculature in both humans (Gorman, 1988; Beaulieu & Gainetdinov, 2011; Bryan et al. 2012) and animal models (Hoshino et al. 1986; Polak et al. 1992; Polak & Drummond, 1993). Additionally, our previous investigation reported that dopamine increased IPAVA recruitment with the concurrent increase in venous admixture (Q˙ s /Q˙ t ) (Bryan et al. 2012).

We hypothesized that exercise-associated increases in dopamine concentration (Hopkins et al. 2009a) are responsible for IPAVA recruitment (Bryan et al. 2012) and correspondingly impair gas exchange with exercise; thus, dopamine blockade during exercise would improve gas exchange and reduce IPAVA recruitment. Additionally, in contrast to their detrimental effect on gas exchange, it has been speculated that these IPAVA may be important to help improve cardiac output (Stickland et al. 2004; La Gerche et al. 2010; Lalande et al. 2012), V˙ O2 max and exercise tolerance by reducing pulmonary vascular resistance, and thereby offloading the right ventricle. Thus, we also hypothesized that despite improving gas exchange, administration of a dopamine blockade would be detrimental to exercise performance.

Methods Ethical approval

This study was approved by the Human Research Ethics Board (Biomedical Panel) at the University of Alberta, and all procedures conformed to the Declaration of Helsinki. All participants gave written, informed consent to participate.

Study design overview

This study consisted of four phases that were separated by at least a week. Phase 1: preliminary testing including pre-screening and progressive incremental exercise test (n = 12). Phase 2: evaluation of pulmonary gas exchange and intrapulmonary arteriovenous anastomosis recruitment during exercise with or without dopamine blockade. To validate this protocol, a separate sample of participants completed an identical protocol, but with placebo at both time points (n = 15). Phase 3: time-to-exhaustion (TTE) trials at 85% of V˙ O2 max , with or without dopamine blockade (order randomized and separated by at least 48 h). Phase 4: incremental exercise test to V˙ O2 max on a cycle ergometer with or without dopamine blockade (order randomized and separated by at least 48 h) (n = 15).

 C 2015 The Authors. The Journal of Physiology  C 2015 The Physiological Society

J Physiol 593.14

Dopamine blockade improves exercise pulmonary gas exchange

Phase 1: preliminary testing

Twelve healthy, non-smoking males (mean age ± SD: 25 ± 6 years, V˙ O2 max : 4.39 ± 0.59 l min−1 ; 56.6 ml kg−1 min−1 ) participated in phases 1–3. Participants completed physical activity readiness questionnaires (PAR-Q), were screened for any cardiopulmonary disorders and/or medications, and were screened for presence of a patent foramen ovale (PFO) with Doppler echocardiography and agitated saline contrast (FASE et al. 2014). No PFOs were observed in any study participant. Additionally, participants were screened for risks associated with ingestion of a telemetry pill. Participants then performed an incremental cycle (Ergoselect II 1200 Ergoline, Blitz, Germany) test to volitional fatigue to determine V˙ O2 max (Encore229 Vmax, SensorMedics, Yorba Linda, CA, USA). The initial power output was set to 50 W and the power output was increased by 25 W every 2 min until ventilatory threshold was reached, as identified by a systematic increase in both the slope of the V˙ E /V˙ O2 and respiratory exchange ratio (RER)–power output curve (Wasserman, 1987). Each stage above ventilatory threshold was characterized by increments of 25 W per minute. The criterion for confirmation of V˙ O2 max required that at least three of the four following conditions were met: volitional exhaustion; a RER greater than 1.1; increases in oxygen consumption less than 100 ml min−1 with further increases in power output; and reaching age-predicted maximum heart rate.

Phase 2: evaluation of gas exchange and intrapulmonary arteriovenous anastomosis recruitment

No less than 48 h after preliminary testing, participants returned to complete the gas exchange/agitated saline contrast echocardiography trial. Participants ingested a placebo pill and were then instrumented with an antecubital intravenous catheter, and a separate catheter was inserted into the radial artery for blood sampling (detailed in ‘Instrumentation and measurements’ below). Echocardiograms were performed at rest and during exercise at 30%, 50%, 70% and 85% of the power output at previously determined V˙ O2 max . Measurements were taken approximately 3 min into each 6 min stage, during steady state exercise. The relative power outputs were chosen in order to characterize the effect of the drug across varying intensities. After the first exercise period, participants ingested a dopamine blocker (metoclopramide, 20 mg orally), and recovered for 60 min before repeating an identical exercise protocol. Participants were blinded to the order of placebo and metoclopramide ingestion.

 C 2015 The Authors. The Journal of Physiology  C 2015 The Physiological Society

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Table 1. Participant characteristics (n = 12) Mean ± SD Age (years) Height (m) Mass (kg) V˙ O2 max (l min−1 ) V˙ O2 max (ml kg−1 min−1 ) V˙ Emax (l min−1 ) Peak power output (W) HRmax (beats min−1 )

25 1.78 75.8 4.39 58.6 152.5 352 184

± ± ± ± ± ± ± ±

6 0.05 7.8 0.59 6.5 32.4 63 9

Range 20–39 1.68–1.87 63.6–91.0 2.96–5.33 46.6–67.3 98.9–217.2 250–425 171–201

V˙ O2 max , maximal O2 consumption; V˙ Emax , maximal ventilation; HRmax , maximal heart rate.

Metoclopramide

Metoclopramide is a dopamine-2 receptor antagonist; the time to peak systemic bioavailabilty of oral metoclopramide is